Clinical significance of DNA methylation in chronic lymphocytic leukemia patients: results from 3 UK clinical trials

Abstract

Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemoimmunotherapy (CIT). DNA methylation profiling can subdivide early-stage patients into naive B-cell–like CLL (n-CLL), memory B-cell–like CLL (m-CLL), and intermediate CLL (i-CLL), with differing times to first treatment and overall survival. However, whether DNA methylation can identify patients destined to respond favorably to CIT has not been ascertained. We classified treatment-naive patients (n = 605) from 3 UK chemo and CIT clinical trials into the 3 epigenetic subgroups, using pyrosequencing and microarray analysis, and performed expansive survival analysis. The n-CLL, i-CLL, and m-CLL signatures were found in 80% (n = 245/305), 17% (53/305), and 2% (7/305) of IGHV-unmutated (IGHV-U) cases, respectively, and in 9%, (19/216), 50% (108/216), and 41% (89/216) of IGHV-M cases, respectively. Multivariate Cox proportional analysis identified m-CLL as an independent prognostic factor for overall survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.87; P = .018) in CLL4, and for progression-free survival (HR, 0.25; 95% CI, 0.10-0.57; P = .002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into 3 first-line UK CLL trials identifies m-CLL as an independent marker of prolonged survival and may aid in the identification of patients destined to demonstrate prolonged survival after CIT.

Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations

“…On these bases, three groups have been identified, namely naïve (n‐CLL), memory (m‐CLL) and intermediate CLL (i‐CLL): n‐CLL mostly included cases with unmutated IGHV , m‐CLL mostly mutated IGHV CLL with low levels of IGHV identity and i‐CLL (11‐32% of all CLL) mostly mutated IGHV cases with intermediate mutational load, but also unmutated IGHV (Queiros et al. , ; Wojdacz et al , ). Thus, although our BL‐CLL would likely fall within the i‐CLL, there is no absolute correspondence between the percentage of IGHV identity and the epigenetic signature.…”

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

“…27 Their prognostic relevance has been validated in retrospective cohorts and clinical trials. [26][27][28] The intermediate epigenetic subtype may be more heterogeneous than initially thought since it includes most stereotype subset 2 cases with aggressive behavior whereas other cases may behave more indolently. The understanding of the biological significance of this subtype requires further analysis.…”

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

“…Recently, Wojdacz et al, applied these epigenetic classifications in the setting of CIT in a retrospective study of 605 treatment-naïve patients enrolled in three chemotherapy and CIT trials from the United Kingdom: (1) CLL4 which compared chlorambucil and fludarabine with or without cyclophosphamide [96], (2) ADMIRE which compared the efficacy of FCR against FCR and mitoxantrone [97], and (3) ARCTIC which compared FCR with FC mitoxantrone, and low-dose rituximab [98]. Multivariate Cox proportional analysis identified m-CLL as an independent prognostic factor for OS (HR, 0.46; 95% CI, 0.24-0.87; p = 0.018) in CLL4, and PFS (HR, 0.25; 95% CI, 0.10-0.57; p = 0.002) in ARCTIC and ADMIRE patients [99].…”